Programmed cell death (apoptosis) is essential in many biological processes, such as embryonic development, immune response, tissue homeostasis, and normal cell turnover. Dysregulation of apoptosis has been an important factor in numerous human diseases, including autoimmune disorder, Alzheimer's and Hunting ton's diseases, heart ischaemia, and various types of cancer. How the apoptotic machinery overrides the cellular survival factors is largely unknown. Using genetic and biochemical approaches, we found that the IkappaB kinase complex (IKK), which is a key regulator of cell survival, is inactivated during cAMP and TNF-alpha induced apoptosis. Specifically, IKK is phosphorylated and inactivated by cAMP- activated protein kinase A. Furthermore, IKK is proteolyzed during TNF-alpha-induced apoptosis. This work is novel as it provides evidence that will delineate the molecular mechanisms by which the apoptotic machinery interplays with cellular survival factors, such as IKK, and should provide information critical to the development of novel strategies in regulating the process of apoptosis in human diseases. Two hypothesis-driven specific aims will be pursued to determine the mechanism through which the apoptotic machinery overrides the protection conferred by the IkappaB kinase and to establish the role of inactivation of the IkappaB kinase in the progression of apoptosis.